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Nature Reviews. Rheumatology Apr 2023Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early... (Review)
Review
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.
Topics: Humans; Mycophenolic Acid; Pulmonary Arterial Hypertension; Phosphodiesterase 5 Inhibitors; Scleroderma, Systemic; Cyclophosphamide; Lung Diseases, Interstitial
PubMed: 36849541
DOI: 10.1038/s41584-023-00909-5 -
Gastroenterology Feb 2021Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for...
BACKGROUND & AIMS
Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)-based screening model for analyzing DILI pathology at organoid resolution.
METHODS
We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform.
RESULTS
HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9-based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis.
CONCLUSIONS
Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.
Topics: Cell Line; Chemical and Drug Induced Liver Injury; Drug Evaluation, Preclinical; Hepatocytes; High-Throughput Screening Assays; Humans; Liver; Organoids; Pluripotent Stem Cells; Toxicity Tests, Acute
PubMed: 33039464
DOI: 10.1053/j.gastro.2020.10.002 -
Chest Dec 2022The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival... (Review)
Review
The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, more opportunities exist for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 Food and Drug Administration-approved medications for PAH in the nitric oxide (NO), endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have fewer interactions of note. Although the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors.
Topics: Humans; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Bosentan; Drug Interactions; Antihypertensive Agents
PubMed: 35841932
DOI: 10.1016/j.chest.2022.06.042 -
Seminars in Fetal & Neonatal Medicine Aug 2022The management of acute hypoxemic respiratory failure (AHRF) in newborns continues to be a clinical challenge with elevated risk for significant morbidities and... (Review)
Review
The management of acute hypoxemic respiratory failure (AHRF) in newborns continues to be a clinical challenge with elevated risk for significant morbidities and mortality, especially when accompanied with persistent pulmonary hypertension of the newborn (PPHN). PPHN is a syndrome characterized by marked hypoxemia secondary to extrapulmonary right-to-left shunting across the ductus arteriosus and/or foramen ovale with high pulmonary artery pressure and increased pulmonary vascular resistance (PVR). After optimizing respiratory support, cardiac performance and systemic hemodynamics, targeting persistent elevations in PVR with inhaled nitric oxide (iNO) therapy has improved outcomes of neonates with PPHN physiology. Despite aggressive cardiopulmonary management, a significant proportion of patients have an inadequate response to iNO therapy, prompting consideration for additional pulmonary vasodilator therapy. This article reviews the pathophysiology and management of PPHN in term newborns with AHRF while highlighting both animal and human data to inform a physiologic approach to the use of PH-targeted therapies.
Topics: Administration, Inhalation; Animals; Humans; Hypertension, Pulmonary; Infant, Newborn; Nitric Oxide; Persistent Fetal Circulation Syndrome; Respiratory Insufficiency; Vasodilator Agents
PubMed: 35688685
DOI: 10.1016/j.siny.2022.101367 -
Frontiers in Pediatrics 2020Persistent pulmonary hypertension of the newborn (PPHN) is one of the main causes of neonatal morbidity and mortality. It is characterized by sustained elevation of... (Review)
Review
Persistent pulmonary hypertension of the newborn (PPHN) is one of the main causes of neonatal morbidity and mortality. It is characterized by sustained elevation of pulmonary vascular resistance (PVR), preventing an increase in pulmonary blood flow after birth. The affected neonates fail to establish blood oxygenation, precipitating severe respiratory distress, hypoxemia, and eventually death. Inhaled nitric oxide (iNO), the only approved pulmonary vasodilator for PPHN, constitutes, alongside supportive therapy, the basis of its treatment. However, nearly 40% of infants are iNO resistant. The cornerstones of increased PVR in PPHN are pulmonary vasoconstriction and vascular remodeling. A better understanding of PPHN pathophysiology may enlighten targeted and more effective therapies. Sildenafil, prostaglandins, milrinone, and bosentan, acting as vasodilators, besides glucocorticoids, playing a role on reducing inflammation, have all shown potential beneficial effects on newborns with PPHN. Furthermore, experimental evidence in PPHN animal models supports prospective use of emergent therapies, such as soluble guanylyl cyclase (sGC) activators/stimulators, l-citrulline, Rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, recombinant superoxide dismutase (rhSOD), tetrahydrobiopterin (BH4) analogs, ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs), 5-HT2A receptor antagonists, and recombinant human vascular endothelial growth factor (rhVEGF). This review focuses on current knowledge on alternative and novel pathways involved in PPHN pathogenesis, as well as recent progress regarding experimental and clinical evidence on potential therapeutic approaches for PPHN.
PubMed: 32850518
DOI: 10.3389/fped.2020.00342 -
Journal of Thoracic Disease Sep 2019Pulmonary arterial hypertension (PAH) is a condition associated with substantial morbidity and mortality. Over the last 25 years there has been a significant evolution... (Review)
Review
Pulmonary arterial hypertension (PAH) is a condition associated with substantial morbidity and mortality. Over the last 25 years there has been a significant evolution in the therapies to treat PAH. These therapies are effective for patients with group I PAH and group IV PH [chronic thromboembolic pulmonary hypertension (CTEPH)]. PAH is characterized by an imbalance of nitric oxide, prostacyclin and endothelin levels, and current pharmacotherapy involves these three pathways. Earlier clinical trials involving PAH-specific therapies evaluated improvements in 6-minute walk time as a primary improvement whereas contemporary trials have been larger and focused on morbidity and mortality reductions. While there may be a role for monotherapy in disease management, most patients should be considered for dual or triple therapy.
PubMed: 31632754
DOI: 10.21037/jtd.2019.09.14 -
Molecular Pharmaceutics Jan 2022In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy,...
In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature (), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [ 2011, 346, 1061-1064] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.
Topics: Bosentan; Calorimetry, Differential Scanning; Dielectric Spectroscopy; Drug Liberation; Spectroscopy, Fourier Transform Infrared; Thermogravimetry; Vitrification; X-Ray Diffraction
PubMed: 34851124
DOI: 10.1021/acs.molpharmaceut.1c00613 -
Biomedicine & Pharmacotherapy =... Feb 2022The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge... (Review)
Review
INTRODUCTION
The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge to improve respiratory function and help patients to survive the most challenging period. Drugs used in targeted therapy of pulmonary arterial hypertension (PAH) appears to be suitable for this task and this article describes their potential for treatment of severe cases of COVID-19.
METHODS
The authors reviewed the following databases for randomized controlled trials, reviews and meta-analyses published up to July 2020: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. The authors included every study contributory to the assessment of the potential of drugs used in targeted PAH therapy in treatment of COVID-19.
RESULTS
Endothelin receptor antagonists, phosphodiesterase 5 inhibitors, riociguat and prostacyclin have proven ani-inflammatory effect and reduce pulmonary artery blood pressure, lung oedema and remodelling. Bosentan shows antiviral properties and sildenafil, as well as epoprostenol, inhibits apoptosis of lung epithelial cells. Among patients with lung lesions the decrease of pulmonary blood pressure can lead to increase of ventilation/perfusion mismatch and decrease of blood oxygenation.
CONCLUSIONS
Among all assessed drugs bosentan, sildenafil and epoprostenol appear to be most promising and a combination of these drugs should be considered due to synergism. The targeted PAH therapy in treatment of COVID-19 associated ARDS could be a useful tool saving lives of patients with severe SARS-CoV-2 infection, however, its introduction should be investigated and monitored very carefully as it can lead to transient deterioration of patient condition.
Topics: Animals; COVID-19; Endothelin Receptor Antagonists; Humans; Phosphodiesterase Inhibitors; Prostaglandins; Pulmonary Artery; Pyrazoles; Pyrimidines; Respiratory Distress Syndrome; COVID-19 Drug Treatment
PubMed: 35062063
DOI: 10.1016/j.biopha.2021.112592